Members of the genus Bacteroides are by far the most abundant Gram-negative bacteria in the human gut microbiome. Recently we used mass spectrometry to examine the outer membrane (OM) proteome and secretome of one of the most commonly studied members of the Bacteroides genus, B. fragilis, grown under laboratory conditions. Although we did not identify any novel secretion pathways, we found that this organism uses a very different range of secretion strategies than Proteobacteria such as E. coli. B. fragilis lacks many of the pathways that are widespread among the Protebacteria (e.g., the type II, III and IV pathways) but produces multiple type I secretion systems simultaneously. B. fragilis also differs dramatically from Proteobacteria in that it produces a large number of lipoproteins that are exposed on the cell surface. The substrates of the type I pathways and the mechanism by which lipoproteins are transported across the OM are unknown. Interestingly, many of the proteins found in the secretome lack significant homology to proteins that are in the Genbank database and presumably have novel functions. Some of our experiments have involved the use of enterotoxigenic (ETBF) strains of B. fragilis that are distinguished by the secretion of a toxin called fragilysin (BFT). Although ETBF strains cause diarrhea and have been associated with colorectal cancer, they have not been well characterized. To facilitate our studies, we recently obtained complete genome sequences of four ETBF strains. The sequences show that these strains exhibit considerable variation at the genomic level. Only a small number of genes that are located primarily in the BFT pathogenicity island (BFT PAI) and the flanking CTn86 conjugative transposon are conserved in all four strains and a fifth strain whose genome was previously sequenced. Interestingly, phylogenetic analysis strongly suggests that the BFT PAI was acquired by non-toxigenic (NTBF) strains multiple times during the course of evolution. At the phenotypic level, we found that the ETBF strains were less fit than the NTBF strain NCTC 9343 and were susceptible to a growth-inhibitory protein that it produces. The ETBF strains also showed a greater tendency to form biofilms, which may promote tumor formation, than NTBF strains. Although the genomic diversity of ETBF strains raises the possibility that they vary in their pathogenicity, our experimental results also suggest that they share common properties that are conferred by different combinations of non-universal genetic elements.